Title : A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase
Abstract :
The intravascular processing of triglyceride-rich lipoproteins depends on lipoprotein lipase ( LPL ) and GPIHBP1 , a membrane protein of endothelial cells that binds LPL within the subendothelial spaces and shuttles it to the capillary lumen
In the absence of GPIHBP1 , LPL remains mislocalized within the subendothelial spaces, causing severe hypertriglyceridemia (chylomicronemia)
The N-terminal domain of GPIHBP1 , an intrinsically disordered region (IDR) rich in acidic residues , is important for stabilizing LPL 's catalytic domain against spontaneous and ANGPTL4-catalyzed unfolding
Here, we define several important properties of GPIHBP1 's IDR
First, a conserved tyrosine in the middle of the IDR is posttranslationally modified by O-sulfation; this modification increases both the affinity of GPIHBP1- LPL interactions and the ability of GPIHBP1 to protect LPL against ANGPTL4-catalyzed unfolding
Second, the acidic IDR of GPIHBP1 increases the probability of a GPIHBP1- LPL encounter via electrostatic steering, increasing the association rate constant (kon) for LPL binding by >250-fold
Third, we show that LPL accumulates near capillary endothelial cells even in the absence of GPIHBP1
In wild-type mice, we expect that the accumulation of LPL in close proximity to capillaries would increase interactions with GPIHBP1
Fourth, we found that GPIHBP1 's IDR is not a key factor in the pathogenicity of chylomicronemia in patients with the GPIHBP1 autoimmune syndrome
Finally, based on biophysical studies, we propose that the negatively charged IDR of GPIHBP1 traverses a vast space, facilitating capture of LPL by capillary endothelial cells and simultaneously contributing to GPIHBP1 's ability to preserve LPL structure and activity